Acute respiratory distress syndrome (ARDS) is a worldwide public health problem with an overall mortality rate of ~30%. Despite recent advances that have improved our understanding of the pathogenesis of ARDS, the development of integrative predictive models for prognostication in the critical care setting and the development of novel pharmacotherapeutics to enhance survival, remain challenging. Activation of the reactive oxygen species (ROS) generating enzyme xanthine oxidoreductase (XOR) plays an essential role in various organ dysfunctions and is an important underlying mechanism of ARDS. Targeting XOR mediated oxidative injury in ARDS has the potential to lead to the design of future diagnostic and prognostic approaches and therapeutic trials. Our group has previously demonstrated inhibition of XOR with allopurinol is protective in rodent models of acute lung injury, ventilator-induced lung injury, and cigarette smoke lung injury. Recently we showed that a novel nonpurine inhibitor of XOR (febuxostat) led to complete abrogation of XOR activity via a resolvin E1 (RvE1) mediated mechanism and significant reduction in LPS-induced mortality. Thus, unlike simple markers of oxidative damage (e.g., GSH/GSSG ratio), XOR plays a novel role in ROS signaling during the resolution of lung injury. In human studies to identify biological and genetic markers predictive of mortality in ARDS, we observed that serum XOR activity was significantly higher in patients with severe sepsis, and highest in sepsis-related ARDS, compared to controls. Furthermore, tests for association with 60-day mortality showed that the missense I703V variant in the gene encoding XOR was significantly associated with enhanced mortality among ARDS patients. These ongoing studies provide the first evidence that XOR represents a novel outcome predictive biomarker and potential therapeutic target for ARDS. Given the unique opportunity this RFA provides, the goal of this exploratory study is to validate the prognostic value of XOR in large scale and well-phenotyped ARDSNet replication cohorts. Specific aims of this application are to: (i) determine whether plasma XOR activity, GSH/GSSG ratio and RvE1 can serve as reliable outcome predictive biomarkers for sepsis-related ARDS in ARDSNet Statins for Acutely Injured Lungs from Sepsis trial (SAILS, n=718); and (ii) test the generalizability of findings from the discovery cohort in a second independent cohort, the ARDSNet Fluid And Catheter Treatment Trial (FACTT, n=880). Results from these studies will provide a unique insight into the role of XOR in the pathogenesis of ARDS, allow more accurate patient stratification for clinical trials, and facilitate precision therapy based on individualized risks.